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121 results for “Allosterism”

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zenodo36/100

Raw NGS Data for "Deep mutational scanning and machine learning reveal structural and molecular rules governing allosteric hotspots in homologous proteins"

This directory contains relevant fastq files used for deep sequencing analysis in the publication “Deep mutational scanning and machine learning reveal structural and molecular rules governing allosteric hotspots in homologous proteins”.  Fastq files are provided for presorted, uninduced and induced populations from DMS experiments of four homologs (TtgR, TetR, RolR, and MphR). Three replicates were performed for each sample. Data analysis of this deep sequencing data was performed using custom scripts, which are described in the methods section of the publication.

opencc-by-4.0Aug 2022View details →

zenodo36/100

A dual selection system for directed evolution to identify allosteric transcription factor PobR variants responsive to different aromatic compounds

This dataset includes all the raw data of our characterization experiments during the work titled “A dual selection system for directed evolution to identify allosteric transcription factor PobR variants responsive to different aromatic compounds”.

opencc-by-4.0Oct 2022View details →

dryad36/100

Comparison of allosteric signaling in DnaK and BiP using mutual information between simulated residue conformations

Molecular Dynamics trajectories of the Hsp70 chaperones DnaK and BiP. System configurations include DnaK or BiP bound to ATP, ATP exchanged to ADP, or the NRLLLTG peptide.

opencc-zeroOct 2022View details →

zenodo36/100

Research data supporting: "A millisecond coarse-grained simulation approach to decipher allosteric cannabinoid binding at the glycine receptor α1"

This repository contains the set of coarse-grained (CG) molecular snapshots representative of the most populated binding modes for glycine receptor (GlyR) in complex with the ligands, along with atomistic backmapped representations. In addition, it contains also CG Martini 3 parameters, charmm36-FF backmapping library file and GROMACS files (itp and gro files) for both ligands.

opencc-by-4.0Jun 2024View details →

dryad36/100

Data from: Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor

Calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) that plays an important role in calcium homeostasis and parathyroid hormone secretion. Here, we present multiple cryo-electron microscopy structures of full-length CaSR in distinct ligand-bound states. Ligands (Ca2+ and l-tryptophan) bind to the extracellular domain of CaSR and induce large-scale conformational changes, leading to the closure of two heptahelical transmembrane domains (7TMDs) for activation. The positive modulator (evocalcet) and the negative allosteric modulator (NPS-2143) occupy the similar binding pocket in 7TMD. The binding of NPS-2143 causes a considerable rearrangement of two 7TMDs, forming an inactivated TM6/TM6 interface. Moreover, a total of 305 disease-causing missense mutations of CaSR have been mapped to the structure in the active state, creating hotspot maps of five clinical endocrine disorders. Our results provide a structural framework for understanding the activation, allosteric modulation mechanism, and disease therapy for class C GPCRs.

opencc-zeroJun 2024View details →

zenodo36/100

Revisiting the allosteric regulation of sodium cation on the binding of adenosine at the human A2A adenosine receptors: insights from Supervised Molecular Dynamics (SuMD) simulations.

SuMD trajectories Videos   Video 1: Sodium binding pathway on the antagonist-bound state of A2AR. The video is composed of four synchronized and animated panels that depict the molecular trajectory obtained by the SuMD simulation considering different aspects of the simulation. The time evolution is reported in a nanosecond. In the first panel (upper-left), the molecular representation of the macromolecular system is shown. The A2AR antagonist-bound state backbone is represented by the ribbon style (cyan colour) and the residues within 4 Å of sodium ion during the entire simulation are dynamically shown. Na+ is rendered showing its VdW volume in yellow. In the second panel (upper-right), the dynamic distance of sodium center of mass (CM) from the A2AR allosteric binding site during the trajectory is reported. In the third panel (lower-left), the MMGBSA energy profile is reported. The animated red circle highlights the value of the corresponding frame. The trend is depicted by a continuous black line obtained by smoothing the raw data (grey circles) using a Bezier curve procedure. In the fourth panel (lower-right) cumulative electrostatic interactions are reported for the 15 A2AR residues most contacted by sodium during the whole simulation.   Video 2: Adenosine different binding pathways collection on the two relevant states of A2AR The video is composed of two panels, which summarizes the recognition process of the adenosine agonist, sampled by means of the supervised molecular dynamics methodology, in the two pharmacologically relevant states of the receptor. In particular, on the right side are shown simultaneously all ten replicas collected starting from the agonist-bound conformation of the A2AR (pink ribbon). The meta-binding site located at the level of the ECL2 and the orthosteric binding site were highlighted. On the left side are represented simultaneously all ten replicas collected starting from the antagonist-bound conformation of the A2AR (cyan ribbon). The meta-binding site located at the level of the ECL2 and the extracellular receptor vestibule were highlighted.   Video 3: Adenosine binding pathway on the agonist-bound state of A2AR. The video is composed of four synchronized and animated panels that depict the molecular trajectory obtained by the SuMD simulation considering different aspects of the simulation. The time evolution is reported in a nanosecond. In the first panel (upper-left), the molecular representation of the macromolecular system is shown. The A2AR agonist-bound state backbone is represented by the ribbon style (pink colour) and the residues within 4 Å of sodium ion during the entire simulation are dynamically shown. Adenosine molecule is rendered by orange carbon atoms and by a transparent surface. In the second panel (upper-right), the dynamic distance of agonist center of mass (CM) from the A2AR allosteric binding site during the trajectory is reported. In the third panel (lower-left), the MMGBSA energy profile is reported. The animated red circle highlights the value of the corresponding frame. The trend is depicted by a continuous black line obtained by smoothing the raw data (grey circles) using a Bezier curve procedure. In the fourth panel (lower-right) cumulative electrostatic interactions are reported for the 15 A2AR residues most contacted by adenosine during the whole simulation.

opencc-by-4.0Jun 2019View details →

zenodo36/100

Ethosuximide: subunit- and Gβγ-dependent blocker and reporter of allosteric changes in GIRK channels

Classical MD simulation of the GIRK2 channel (PDB: 3SYA) in a POPC membrane in presence of the inhibitor Ethosuximide.  The scope of the study was to find the ETX binding site. We conducted 5 (run1-5 ) runs each 1.5 μs long. The upload contains a .gro, .a tpr, and an .xtc file of each run.  The .xtc files were processed before the upload and contain every 100th frame of the original data. The corresponding manuscript was uploaded on the bioRxiv (doi: https://doi.org/10.1101/2024.06.04.597296 ).   Simulation paramters: FFs: Amber99sb, Berger lipids, SPC/E water, GAFF2 (ETX), corrected monovalent Lennard–Jones parameters for ions Software: Gromacs 5.1.2. Time step: 2fs Lennard–Jones / electrostatic interactions cut-off: 1.0 nm Long-range electrostatic interactions: Particle-Mesh Ewald algorithm  Bonds were constrained with the LINCS algorithm Temperature: 310 K, V-rescale, τ = 0.1 ps Pressure: 1 bar,  Parirnello-Rahma, τ = 2 ps   Composition of the system: 1 GIRK2 channel (PDB: 3SYA), consisting of 4 chains A, B, C, D 4 PIP2 bound to the channel, residue name MOL 588 POPC Berger lipids, residue name POPC 60897 SPC/E water, residue name SOL 322 K+,  residue name K 274 Cl-, residue name CL 10 R-Ethosuximide, residue name ETR 10 S-Ethosuximide, residue name ETS

opencc-by-4.0Nov 2024View details →

dryad36/100

Data from: Positive allosteric modulation of the α7 nicotinic acetylcholine receptor as a treatment for cognitive deficits after traumatic brain injury

Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly vulnerable to TBI. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer's disease and schizophrenia. Positive allosteric modulation of α7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in naïve animals and healthy human subjects. Therefore, we hypothesized that targeting the α7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the α7 nAChR may be a novel therapeutic to improve cognition after TBI.

opencc-zeroJun 2021View details →

zenodo36/100

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

Amyloid deposition of the microtubule-associated protein tau is a unifying theme in a multitude of neurodegenerative diseases. Disease-associated missense mutations in tau are associated with frontotemporal dementia (FTD) and enhance tau aggregation propensity. However, the molecular mechanism of how mutations in tau promote tau assembly into amyloids remains obscure. There is a need to understand how tau folds into pathogenic conformations to cause disease. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation. We use recombinant protein and synthetic peptide systems, computational modeling, cross-linking mass spectrometry, and cell models to investigate the mechanism of spontaneous aggregation of the S320F FTD-tau mutant. We discover that the S320F mutation drives the stabilization of a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif. We identify a suppressor mutation that reverses the S320F aggregation phenotype through the reduction of S320F-based hydrophobic clustering in vitro and in cells. Finally, we use structure-based computational design to engineer rapidly aggregating tau sequences by optimizing nonpolar clusters in proximity to the S320 site revealing a new principle governing the regulation of tau aggregation. We uncover a mechanism for regulating aggregation that balances transient nonpolar contacts within local protective structures or in longer-range interactions that sequester amyloid motifs. The introduction of a pathogenic mutation redistributes these transient interactions to drive spontaneous aggregation.  We anticipate that more profound knowledge of this process will permit control of tau aggregation into discrete structural polymorphs to aid the design of reagents that can detect disease-specific tau conformations.

opencc-by-4.0Feb 2023View details →

zenodo36/100

Datasets for Application of particle swarm optimization to understand the mechanism of action of allosteric inhibitors of the enzyme HSD17ß13

Datasets used in the publication ' Application of particle swarm optimization to understand the mechanism of action of allosteric inhibitors of the enzyme HSD17ß13'

opencc-by-4.0Mar 2023View details →

zenodo36/100

MONOTERPENOID ARYL HYDROCARBON RECEPTOR ALLOSTERIC ANTAGONISTS PROTECT AGAINST ULTRAVIOLET SKIN DAMAGE IN FEMALE MICE

Source data for publication of paper in Nature Communication. Current phase - final revision - mandatory deposition of the data

opencc-by-4.0Mar 2023View details →

zenodo36/100

Allosteric activation of cell wall synthesis during bacterial growth

This repository contains single-molecule FRET data related to this manuscript organized by figure. Note that data that appear both in the main and in the supplementary figures are provided only once, in the relevant main figure folders. Each figure folder contains all relevant datasets, deposited as zipped folders with pre-processed raw trajectories in the .dat format. These trajectories list donor excitation/donor emission (column 1) and donor excitation/acceptor emission (column 2) values as a function of time, and can be visualized and further processed using either custom code or the publicly available ebFRET software (http://ebfret.github.io/).

opencc-by-4.0Apr 2023View details →

zenodo36/100

Data for "Absolute binding free energy calculation based on the fragment molecular orbital method and its application in designing novel SHP-2 allosteric inhibitors"

Data for publication "Absolute binding free energy calculation based on the fragment molecular orbital method and its application in designing novel SHP-2 allosteric inhibitors".All structures of complex and input files for FMO , FMO/SMD , FMO/PCM , and COSMO calculation are provided .

opencc-by-4.0Sep 2023View details →

zenodo36/100

DATASET: What is allosteric regulation? Exploring the exceptions that prove the rule!

This dataset contains the Kineticscope simulations and schemes used to generated the kinetic populations figure. Kinetiscope is available from <a href="https://hinsberg.net/kinetiscope/">https://hinsberg.net/kinetiscope/</a>.

opencc-by-4.0Oct 2023View details →

dryad36/100